Sigma receptors (Rs), were initially proposed as opioid, and later phencyclidine receptors, and were finally demonstrated to represent unique binding sites in mammalian brain and peripheral tissues that are expressed throughout the CNS and have been implicated in a variety of physiological functions and disease states. Two subtypes of Rs have been distinguished molecularly and pharmacologically. Although the psychomotor stimulant and reinforcing effects of cocaine are primarily mediated through stimulation of dopamine (DA) neurotransmission by inhibiting dopamine reuptake, cocaine also shows a moderate affinity for Rs, and it has been suggested that some cocaine-induced effects could be mediated or modulated by its own actions at 1 and/or 2 receptor subtypes. In addition several studies have shown antagonism of various effects of cocaine by R antagonists, and chronic exposure to cocaine has neuroplastic effects that are prevented by the R antagonists. For example, in a recent study we showed that the R antagonist, AC927 (1-(2-phenethyl)piperidine oxalate), significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. In addition, subchronic administration of AC927 attenuated cocaine-induced place conditioning in mice, at doses that alone had no effects. AC927 differed from other R antagonists in partially substituting for the discriminative-stimulus effects of cocaine. Further, AC927 was self-administered in non-human primates, though to a lesser extent than was cocaine. Because R antagonists have been reported to block reinforcing effects of cocaine assessed using place conditioning, we further examined the effects of R antagonists using cocaine self-administration procedures as another means of assessing their effect on cocaine reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj of cocaine;lower response rates were maintained at higher and lower doses of cocaine. Pre-session treatment with R antagonists (BD 1008, BD 1047, BD 1063) had no effect on cocaine self administration across the range of behaviorally active doses. These results suggest a difference in reinforcing effects as assessed by place conditioning and self administration. Surprisingly, R agonists, DTG and PRE-084, dose-dependently shifted the cocaine self-administration dose-effect curve leftward in a manner that resembled what was found with standard dopamine-uptake inhibitors such as WIN 35,428. those results suggested reinforcing effects of the R agonists, which were confirmed by testing their substitution in rats trained to self administer cocaine. Treatment with the R antagonists dose-dependently decreased the self administration of DTG and PRE-084, in contrast to their inactivity against cocaine self-administration. Although R antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at Rs. However, the self-administration of R agonists in cocaine-trained subjects, facilitation of cocaine self-administraton by R-agonist pretreatment, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically-mediated actions and R-mediated actions of the drugs. Further studies of selective R agonists, DTG and PRE-084, examined their cocaine-like effects in rats trained to discriminate injections of cocaine from saline. These studies assessed the similarity of the subjective effects of R agonists to those of cocaine. Standard dopamine uptake inhibitors (WIN 35 428, methylphenidate), but neither PRE-084 nor DTG fully substituted for cocaine. The absence of cocaine-like effects of R agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). These results demonstrate that the reinforcing effects of the selective R agonists are not due to an overlap of subjective effects with those of cocaine, and are consistent with a reinforcement mechanism for R agonists separate from that typically studied with psychomotor stimulant drugs. Receptor-binding studies have identified two subtypes of Rs, 1 and 2. Involvement of both subtypes has been implicated in substance-abuse disorders. Like cocaine, the non-selective 1/2R agonist DTG, and the selective 1R agonist PRE-084 dose-dependently increased DA in the shell of the nucleus accumbens and area of the brain critical for the reinforcing effects of abused drugs. However, their maximal effects were less than those of cocaine. DTG-induced stimulation of DA was antagonized by the 1/2R antagonist, BD 1008, and by the preferential 2R antagonist SN79, but not by the preferential 1R antagonist, BD 1063. Effects of neither PRE-084 nor cocaine were antagonized by either BD1063 or BD1008. Thus, stimulation of DA by R agonists in a brain area involved in the reinforcing effects of cocaine was demonstrated. The effects appear to be mediated by 2Rs rather than 1Rs. However Rs are not likely involved in mediating the acute cocaine- and PRE-084-induced stimulation of DA transmission. Different mechanisms might underlie the dopaminergic and reinforcing effects of R agonists suggesting a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders. The suggestion that the reinforcing effects of 1R agonists are DA independent is being pursued in pharmacology studies of drug antagonism. Comparable response rates were maintained in two groups of rats: one with cocaine injection as the reinforcer and the other (after a history of cocaine self administration) with PRE-084. As expected cocaine self administration was antagonized by the DA antagonists, SCH 39166, L741,626, and haloperidol. As previously found, cocaine self administration was insensitive to the R antagonist, BD1063. In contrast, PRE-084 self administration was insensitive to the DA antagonists, SCH 39166 and L741,626, and dose-dependently blocked by the R antagonists, BD1063. Taken together many of the present results are consistent with the hypothesis that reinforcing effects of the selective R agonists are obtained in cocaine experienced subjects and are mediated by reinforcement mechanisms that differ from those typically studied with psychomotor stimulant drugs. Future studies will address the importance of this novel reinforcement mechanism in the abuse of psychomotor stimulant drugs.
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